# US 10,479,838 B2 · Antibodies to CD40 with enhanced agonist activity

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- Number: US 10,479,838 B2
- Document ID: US10479838B2
- Status: Granted
- Kind: B2
- Application number: 15/195,098
- Filed: 2016-06-28
- Published: 2016-12-29
- Granted: 2019-11-19
- Earliest claimed: 2015-06-29
- Assignees: Bristol-Myers Squibb Company; The Rockefeller University
- Applicants: The Rockefeller University; Bristol-Myers Squibb Company
- Inventors: Jeffrey V. Ravetch; Rony Dahan; Bryan C. Barnhart; Brigitte Devaux; Aaron P. Yamniuk; Shannon L. Okada; Brenda L. Stevens
- Web page: https://patentgrep.com/patent/US10479838B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/04: Immunostimulants
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/72: Increased effector function due to an Fc-modification
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Provided herein are agonistic antibodies, or antigen binding portions thereof, that bind to human CD40. Such antibodies optionally comprise Fc regions with enhanced specificity for FcγRIIb. The invention also provides methods of treatment of cancer or chronic infection by administering the antibodies of the invention to a subject in need thereof.

## Claims

### Claim 1

An isolated antibody or antigen binding portion thereof that specifically binds to human CD40 comprising:
the CDRs of antibody 12D6-24 wherein CDRH 1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO: 12 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO: 9, wherein the antibody further comprises an Fc region modified to enhance specificity of binding to FcγRIIb, wherein the Fc region comprises a sequence selected from the group consisting of SE (SEQ ID NO: 66), SELF (SEQ ID NO: 67), P238D (SEQ ID NO: 68), V4 (SEQ ID NO: 69), V4 D270E (SEQ ID NO: 70), V7 (SEQ ID NO: 71), V8 (SEQ ID NO: 72), V9 (SEQ ID NO: 73), V9 D270E (SEQ ID NO: 74), V11 (SEQ ID NO: 75), and V12 (SEQ ID NO: 76).

### Claim 2 (depends on 1)

The antibody of claim 1 comprising:
the heavy and light chain variable regions of antibody 12D6-24 comprising residues 1-119 and 1-112 of SEQ ID NO: 12 and SEQ ID NO: 9, respectively.

### Claim 3 (depends on 1)

The antibody of claim 1 exhibiting an A/I ratio of less than 5.

### Claim 4 (depends on 3)

The antibody of claim 3 exhibiting an A/I ratio of less than 1.

### Claim 5 (depends on 1)

The antibody of claim 1 comprising heavy and light chain sequences selected from the groups consisting of:
a) the heavy and light chains of antibody 12D6-24-P238D comprising the sequences of SEQ ID NO:13 and SEQ ID NO:9, respectively;
b) the heavy and light chains of antibody 12D6-24-SE comprising the sequences of SEQ ID NO:14 and SEQ ID NO:9, respectively;
c) the heavy and light chains of antibody 12D6-24-SELF comprising the sequences of SEQ ID NO:15 and SEQ ID NO:9, respectively;
d) the heavy and light chains of antibody 12D6-24-V4 comprising the sequences of SEQ ID NO:16 and SEQ ID NO:9, respectively;
e) the heavy and light chains of antibody 12D6-24-V4 D270E comprising the sequences of SEQ ID NO:17 and SEQ ID NO:9, respectively;
f) the heavy and light chains of antibody 12D6-24-V8 comprising the sequences of SEQ ID NO:18 and SEQ ID NO:9, respectively;
g the heavy and light chains of antibody 12D6-24-V9 comprising the sequences of SEQ ID NO:19 and SEQ ID NO:9, respectively;
h) the heavy and light chains of antibody 12D6-24-V9 D270E comprising the sequences of SEQ ID NO:20 and SEQ ID NO:9, respectively;
i) the heavy and light chains of antibody 12D6-24-V11 comprising the sequences of SEQ ID NO:21 and SEQ ID NO:9, respectively; and
j) the heavy and light chains of antibody 12D6-24-V12 comprising the sequences of SEQ ID NO:22 and SEQ ID NO:9, respectively.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising:
a) the antibody, or antigen binding portion thereof, of claim 1; and
b) a carrier.

### Claim 7 (depends on 6)

A method of stimulating a T-cell mediated immune response in a subject comprising administering to the subject the pharmaceutical composition of claim 6.

### Claim 8 (depends on 7)

The method of claim 7, wherein the subject has a cancer and a T-cell mediated immune response against the cancer is stimulated.

### Claim 9 (depends on 7)

The method of claim 7, wherein the subject has a chronic viral infection and a T-cell mediated immune response against the viral infection is stimulated.

### Claim 10 (depends on 8)

The method of claim 8, wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, uterine/cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.